New drugs

(Aust Prescr 1996;19:81-3)

Some of the views expressed in the following notes on newly approved products should be regarded as tentative, as there may have been limited published data and little experience in Australia of their safety or efficacy. However, the Editorial Executive Committee believes that comments made in good faith at an early stage may still be of value. As a result of fuller experience, initial comments may need to be modified. The Committee is prepared to do this. Before new drugs are prescribed, the Committee believes it is important that full information is obtained either from the manufacturer's approved product information, a drug information centre or some other appropriate source.

Abciximab

ReoPro (Eli Lilly Australia)
2 mg/mL in 5 mL and 20 mL glass vials

Indication: coronary angioplasty
Abciximab has been approved for patients who have a high risk of developing acute vessel closure as a complication of coronary angioplasty. Patients who are especially at risk include those with a myocardial infarction or unstable angina, and those with lesions which have particular morphological characteristics. Abciximab is added to the routine use of heparin and aspirin.

The beneficial effects of abciximab are due to its inhibition of platelet aggregation. Abciximab is an IgG antibody directed against glycoprotein receptors on the surface of platelets. It prevents fibrinogen from binding to activated platelets.

Abciximab is given as an intravenous bolus followed by an infusion over 12 hours. The drug binds rapidly to platelets and blocks at least 80% of the receptors. During the infusion, the bleeding time can exceed 30 minutes.

In a multicentre, double-blind trial, 2099 patients undergoing coronary angioplasty were given aspirin, heparin and either abciximab or a placebo. The endpoints of the study were death, myocardial infarction, coronary artery bypass surgery or a need for revascularisation. In the first 48 hours after angioplasty or atherectomy, patients given placebo were more likely to have had these adverse outcomes.

As at least 30% of patients develop a restenosis within 6 months, the outcomes were also analysed after that interval. Fewer patients in the treatment group had an infarction or required revascularisation. The absolute difference in major ischaemic events/revascularisation was 8.1% (35.1% placebo vs. 27% active treatment).¹

Although abciximab reduces restenosis, it can also cause major bleeding in 10-20% of patients. In the study1, the patients given abciximab had a significant increase in bleeding complications in the first 48 hours. This may be because platelet function takes 24-48 hours to recover after the infusion stops. The bleeding is usually from the femoral artery access site; however, intracranial, retroperitoneal, gastrointestinal or genitourinary haemorrhage can occur. Some patients will develop thrombocytopenia.

At present, it is not clear if the cost of treatment (approximately $1500 per patient) and its complications will be offset by the benefits of abciximab.

R E F E R E N C E
1. EPIC Investigators. Randomised trial of coronary intervention with antibody against platelet 11b/111a integrin for reduction of clinical restenosis: results at six months. Lancet 1994;343:881-6.

Gemcitabine hydrochloride

Gemzar (Eli Lilly Australia)
200 mg in 10 mL vials and 1 g in 50 mL vials

Indication: non-small cell lung cancer
Unresectable non-small cell lung cancer has been treated with radiotherapy, but there may also be a role for gemcitabine. Gemcitabine is an analogue of cytarabine. It kills cells by inhibiting DNA synthesis, so it also causes bone marrow suppression.

The drug is given weekly, by intravenous infusion, for 3 weeks. There is a one-week rest period and then the cycle is repeated. The dose is adjusted according to the effect on white blood cells and platelets. Intracellular metabolism produces active nucleosides. While these intracellular metabolites are not found in the urine, only 10% of the drug is excreted unchanged. The main metabolite found in the urine is inactive.

Patients with unresectable non-small cell lung cancer have a poor prognosis. Although approximately 20% of patients will respond to gemcitabine, a beneficial effect on survival has not been shown.

Many patients will experience adverse reactions. In addition to leucopenia, thrombocytopenia and anaemia, gemcitabine can cause rashes, oedema, haematuria, flu-like symptoms, nausea and vomiting.

Levocabastine hydrochloride

Livostin (Janssen-Cilag)
0.5 mg/mL as nasal spray and eye drops

Indication: allergic rhinitis/conjunctivitis
Levocabastine is a H₁ receptor antagonist. It has a rapid onset of action and the antihistamine effect lasts for several hours.

In patients with seasonal allergic rhinitis, the nasal spray is more effective than placebo, but less effective than beclomethasone for the relief of symptoms. Levocabastine and sodium cromoglycate are of similar efficacy. Although similar trends may apply in cases of perennial allergic rhinitis, there is less supporting evidence.

The eye drop formulation is more effective than placebo in relieving the symptoms of seasonal allergic conjunctivitis. Levocabastine eye drops instilled twice a day are also as effective as sodium cromoglycate given 4 times a day.

Most adverse effects are due to local irritation of the eye or nose. However, up to 60% of the ocular dose and up to 80% of the nasal dose are absorbed. This absorption creates the potential for systemic adverse effects and patients should be informed of the possible risk of sedation.

While some patients may prefer levocabastine to oral antihistamines, safety and efficacy have not been established beyond one month of therapy. Therefore, levocabastine has only been approved for short-term use.

Stavudine

Zerit (Bristol-Myers Squibb)
15 mg, 20 mg, 30 mg and 40 mg capsules

Indication: HIV infection
Stavudine is an analogue of thymidine, similar to zidovudine. These nucleoside analogues act by inhibiting the reverse transcriptase of the human immunodeficiency virus.¹

The drug is given twice a day by mouth. It is well absorbed, but absorption is reduced by high-fat meals. The significance of this reduced absorption is unclear as the relationship between plasma concentrations and antiviral activity is unknown. The metabolism of stavudine is also unknown, but as 40% of total clearance is by the kidneys, dose reductions are required if renal function is impaired. Stavudine has a half-life of approximately 1.5 hours.

As experience with stavudine is limited, its role in therapy is not yet clear. It has been approved for the treatment of HIV infection in adults. Although the safety and efficacy of stavudine has not been established in children, the drug is approved for use in children aged 12 years and over.

Many of the patients studied in trials of stavudine had previously taken zidovudine. Stavudine may therefore have a role in patients who are unable to tolerate or are not responding to zidovudine. The efficacy of stavudine has mainly been assessed by its effects on CD₄ lymphocyte counts, HIV titres in mononuclear cells and p24 antigen concentrations.

Patients should be informed about the symptoms of peripheral neuropathy as this is the most common toxicity. Approximately 40% will develop symptoms and 21% will require their treatment to be interrupted. Other adverse events occurring in clinical trials include neutropenia, anaemia, altered liver function tests and pancreatitis.

R E F E R E N C E
1. Locarnini S. Antiviral drugs - mechanisms of action. Aust Prescr 1993;16:78-81.

Venlafaxine hydrochloride

Efexor (Wyeth Australia)
37.5 mg, 50 mg and 75 mg tablets

Indication: depression
Venlafaxine is an antidepressant structurally and chemically unrelated to all other antidepressant medications. It is thought to potentiate neurotransmitter activity by inhibiting the reuptake of serotonin and noradrenaline. Depressed patients taking venlafaxine are more likely to improve than those taking placebo. Venlafaxine appears to be of comparable efficacy to the tricyclic antidepressants.

After absorption, venlafaxine undergoes extensive first-pass metabolism which produces an active metabolite. The small amount of unchanged drug and the liver metabolites are mainly excreted in the urine. The halflife is considerably shorter than most of the other currently available antidepressants, being 5 hours for the parent compound and 11 hours for the metabolite. Clearance can be reduced by hepatic or renal dysfunction. For most patients, the minimum effective dose is 75 mg a day given in divided doses with food.

During shortterm studies, approximately 28% of patients discontinued treatment a similar rate to other antidepressants. Adverse effects which were more frequent with venlafaxine than placebo included nausea, somnolence, dizziness, dry mouth and sweating. As animal studies suggest that venlafaxine has no affinity for muscarinic receptors, it may cause fewer anticholinergic adverse effects than other antidepressants.

There is little information about interactions between venlafaxine and other drugs. It is recommended that venlafaxine should not be given less than 14 days after ceasing treatment with a monoamine oxidase inhibitor.

There are limited data about the longterm use of venlafaxine. When ceasing treatment, venlafaxine should be gradually withdrawn over 7 days if it has been taken for more than 6 weeks.

NEW COMBINATIONS

Oestradiol/norethisterone acetate

Kliogest (Novo Nordisk Pharmaceuticals)
tablets containing 2 mg oestradiol with 1 mg norethisterone acetate

Oestradiol valerate and oestradiol valerate/cyproterone acetate

Climen (Schering)
11 tablets containing 2 mg oestradiol valerate and>br> 10 tablets containing 2 mg oestradiol valerate with 1 mg cyproterone acetate

NEW STRENGTHS

Ipratropium bromide

Atrovent Nasal Aqueous Spray (Boehringer Ingelheim)
300 microgram/mL delivering 21 microgram/actuation

NEW FORMULATIONS

Cefpodoxime proxetil

Orelox (Hoechst Marion Roussel)
40 mg/5 mL granules for paediatric suspension

NEW PROPRIETARY BRANDS

Cyproterone acetate

Cyprone (Alphapharm)
50 mg tablets

Piroxicam

Candyl-D (Douglas Pharmaceuticals)
10 mg and 20 mg dispersible tablets

Verapamil hydrochloride

Anpec SR (Alphapharm)
240 mg sustained release tablets